Cytokines are secreted regulators that control the production, maturation and functional activation of bloodcells that are essential for hemostasia and host defense from infection. These beneficial actions of cytokineshave been harnessed clinically, for example the use of G-CSF to promote recovery of white blood cells inpatients receiving cancer chemotherapy, or EPO to treat anemia. In addition, deregulation of cytokines, theirreceptors or intracellular signal transduction pathways is associated with autoimmunity and cancer. Theimportance of negative regulation of cytokine signaling cascades has come clearly into focus with ouridentification and characterization of the family of Suppressors of Cytokine Signaling (SOCS) proteins. Ourlong-term objective is to identify the specific cytokines regulated by individual SOCS proteins and the cellsand biological systems dependent on SOCS regulation. We seek to define the biochemical basis of SOCSaction via elucidation of the structures of, and physical interactions between, SOCS proteins and thesignaling machinery and to define the disease contexts in which manipulation of SOCS proteins may proveclinically beneficial. Our focus here is on S0CS3, the key negative regulator of G-CSF and IL-6 that isrequired to prevent spontaneous inflammatory disease. Applying a multidlsciplinary approach employingbiochemical and structural biological tools, cell biology and genetically modified mouse models, our majorgoals are: defining the specific roles of S0CS3 in relevant mouse models of inflammation and hematopoieticmalignancy, understanding the shared or overlapping physiological roles of S0CS3 with other SOCS familymembers, and defining the functions of protein domains within the overall actions of S0CS3, along withdiscovery of novel protein targets of S0CS3 action.

Public Health Relevance

Successful outcomes will provide new strategies for intervention in cytokine-related diseases, particularlycancer and inflammation.